The following background information is provided to assist the reader to understand the invention disclosed below and the environment in which it will typically be used. The terms used herein are not intended to be limited to any particular narrow interpretation unless clearly stated otherwise in this document.
Ultrasound is a well-known technique that uses sound waves to produce on a display screen images of the region of the body being scanned. It does this by emitting ultrasonic waves—at frequencies in the range of 1 to 20 Megahertz (MHz)—into the body and then producing an image from the waves that are reflected by the tissues in the area being scanned. Although other techniques (e.g., computerized tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA)) can be used to produce images of the body, they do so using extremely expensive equipment. In addition, although CT and PET scanning techniques are considered reasonably safe, they obtain images using ionizing radiation, which can pose a risk to human health particularly upon repeated exposure. The sound waves used during an ultrasound procedure, however, are comparatively risk free.
An ultrasound system typically features a display screen, a control unit, and a transducer, which is often referred to as a probe. The transducer transmits and receives ultrasonic energy along a beam. When ultrasonic waves traveling through one tissue hit a boundary with a second tissue, some of them pass into the second tissue, and some are reflected back to the transducer. The exact fraction of the energy that is absorbed or reflected depends on how different the two tissues are from each other. This is known as the acoustic impedance of the tissue, and is related to the density and composition of the tissue and the speed of sound through it. The greater the difference in impedance between two tissues, the more sound energy will be reflected back at their interface. Interfaces between solid tissues, the skeletal system, and various organs, and even tumors, are readily imaged by ultrasound techniques. Ultrasound thus yields especially sharp images where there are distinct variations in the density or compressibility of the tissue, such as at the tissue interfaces. If the acoustic impedance difference is too great, however, a good image may not be created because too much energy is reflected.
A transducer is typically equipped with both a transmitter and a receiver of ultrasonic waves. Because air and skin have different ultrasonic impedances, a coupling medium (i.e., a layer of gel) is applied to the region of interest to match the impedance of the piezoelectric crystals in the transducer more closely to the impedance of the skin of the patient, thus allowing the ultrasonic waves to enter the body more readily. In operation, the transducer is periodically driven by an electrical pulse, which causes its transmitter to periodically emit a pulse of ultrasonic energy. During a scanning procedure, as the transducer is moved over the region of interest, only those waves that reflect or scatter at the tissue interfaces are picked up by the receiver. Because the transducer transmits and receives ultrasonic waves primarily along a beam, when an echo is received, the interface causing the echo must therefore be within the path of the beam. In addition, the time that the reflected energy or “echo” takes to arrive at the receiver from a given interface depends on the distance between the interface and the surface of the skin, which provides an indication of the depth of the interface. Depending on how it is configured, the control unit of an ultrasound system may be programmed to process the information obtained during a scan in different ways to provide different images (e.g., A-Scans (Amplitude Scans), B-Scans (Brightness), Real-Time B-Scans, and Doppler) of the observed region on the display screen. Differences in the reflected energy are typically made to appear on the display screen as different colors or different shades of gray.
Ultrasound provides images of sufficiently high quality for many diagnostic applications. In certain types of applications, however, a contrast fluid or “medium” will be administered to the patient to enhance the quality of the images that can be obtained during a scanning procedure. A contrast medium contains what is referred to as a contrast agent, which can take the form of suspended or dispersed entities such as microbubbles, microspheres or solid particles. Soon after injection into a patient, the contrast medium reaches the region of interest. In response to the incident ultrasonic waves, the contrast medium yields a pronounced difference in the reflected energy between the contrast agent contained therein and the surrounding tissues. In this way, the contrast agent serves to increase or enhance the image contrast between the tissues in the region of interest, and thereby enhance the resolution of the images obtained during the scanning procedure. Besides being used for imaging, contrast media can also be injected into various body cavities or tissues as necessary for diagnostic or therapeutic procedures.
Contrast media are particularly well suited for studying the adequacy of blood flow in the organs and other tissues. For example, when a contrast medium is injected into the blood stream, the reflected ultrasound energy will be Doppler shifted due to the flow of blood in which the contrast agents are being carried. This Doppler shift allows the speed, and thus the adequacy, of the blood flow to be ascertained quite readily. Contrast agents can also be excited so that they radiate ultrasonic energy at a harmonic of the incident ultrasonic energy. Harmonic imaging with the use of a contrast medium can be used to increase the effectiveness of the contrast agent.
The most commonly used contrast media typically employ microbubbles (i.e., small bubbles typically 3-10 microns (μm) in diameter) as the contrast agent. Typically containing a gas such as air, a perfluorocarbon, or carbon dioxide, microbubbles are formed with the use of foaming agents, surfactants or encapsulating chemicals. Once injected intravenously, the microbubbles provide a substance in the blood that is of a different density and a much higher compressibility than the flowing blood and adjacent tissues. Microbubbles thus constitute an excellent means for reflecting and scattering ultrasound energy, which makes them easily imaged with ultrasound techniques. The contrast media can also be excited in such a way that the microbubbles are destroyed, and the energy released during the popping of the microbubbles is used to create the image.
Contrast media suitable for use in ultrasound are supplied in a number of forms. U.S. Pat. No. 5,605,673 to Schutt et al. and U.S. Pat. No. 6,317,623 B1 to Griffiths et al., incorporated herein by reference, discuss many of these in detail. Some contrast media take the form of powders to which a liquid is added just before use. The particles in the powder cause gas microbubbles to coalesce around them. The powder must be mixed with a liquid, and the mixture agitated with a precise degree of vigor, to obtain microbubbles having optimum characteristics. Another type of contrast medium supplied in liquid form requires hypobaric or pressure activation. A third type of contrast medium is a liquid that must be agitated vigorously. There are no solid particles to act as nucleation sites, but the liquid is a mixture of several components that make relatively stable small bubbles. A fourth type of contrast medium uses “hard” spheres filled with a gas. These contrast media are typically supplied as a powder that is mixed with a liquid. The goal is to suspend the spheres in the liquid without breaking them. Though such spheres have a shell that is hard compared to a liquid, they are very small and relatively fragile. It is possible for the solid particles themselves to act to scatter ultrasonic energy, but the acoustical properties of the solid spheres are not as different from water as those of a gas. Solid particles are therefore not as efficient or effective as scatterers of ultrasonic energy. Solid particles, however, have the advantage that they are much more robust and longer lasting.
FIG. 1 illustrates an example of the current practice in ultrasound imaging. The contrast medium often comes within a single-use vial 10 in which a fluid and an appropriate gas have been sealed. After mixing or preparation as described above, any excessively large bubbles are removed and the resulting contrast medium is drawn into a syringe 11 or other container for injection into the patient 20. An intravenous catheter 22 is inserted by a nurse or other qualified technologist into a suitable vessel, normally a vein in the patient's arm. Syringe 11 is then placed on a pump 12 or other type of pressurizing device, with the pump having been programmed for the procedure through a user interface 14. The syringe 11 is then connected to catheter 22 via tubing 18, with the tubing 18 and catheter 22 having been previously filled with saline to eliminate all the air therein to prevent any chance of an air embolism. Once activated and operating according to its programming, the pump 12 injects the contrast medium into the vein. Diluted by the blood, the contrast medium soon passes through the chambers of the right heart, the lungs, the chambers of the left heart, and eventually to the region of interest. During the scanning procedure, the transducer 24 is moved over the region of interest. Processing the reflected ultrasonic waves according to known techniques, the ultrasound imager 26 then produces images of the region of interest on its display screen 26b. 
There are several disadvantages inherent to the prior art practices described above. Variations in the preparation process (e.g., mixing, agitation, pressure activation, etc.) can lead to variations in the concentration and size distribution of the microspheres or particles within the contrast medium, which can adversely affect the resulting imaging procedure. There can also be degradation from storage of the delicate powders. After preparation, most contrast agents deteriorate over time, causing the concentration of the microbubbles or particles to decrease and their size to vary with time. Contrast agents in the form of microbubbles are also adversely affected by pressure before or during administration. The gas in the microbubbles tends to diffuse into the carrier liquid. The smaller the microbubble, the greater the pressure it experiences due to surface tension (Laplace pressure) and the faster its gas diffuses into the liquid. Gas can also diffuse into a microbubble, causing it to grow unacceptably large. These problems affect the concentration and the size of the microbubbles within the contrast medium.
Microbubbles are mechanically fragile and thus can be destroyed during both injection and storage. The pressure at which the injections are currently given must be severely limited to prevent destruction of the microbubbles. Because microbubbles are lighter than the liquid carrying them, they tend to rise and separate from the liquid between creation and injection. This leads to non-uniform or even non-diagnostic bubble densities. To overcome this, various methods have been devised for agitating the microbubbles between the time they are created and the moment at which they are injected into the patient. WO 00/53242A1 by Trombley et al) (see also WO 99/27981), incorporated herein by reference, discloses one (or more) such methods of agitation.
Another shortcoming of the prior art practice relates to the limited lifetime of such contrast media and the need for sterile conditions in handling and administration. A contrast medium must be used soon after it is mixed or otherwise prepared. When the imaging procedure requires less contrast media than what a vial provides, the unused portion is routinely discarded, which represents a waste of money. Conversely, when more contrast media is required, a new vial must be mixed in the middle of an imaging procedure. Not only does this prove inconvenient and distracting to the technologist, it takes a significant amount of time, which also translates into increased costs.
In an alternative, U.S. Pat. No. 6,231,513 B1 to Daum et al. teaches an apparatus and method to create carbon dioxide bubbles within the blood vessel being imaged. There is a benefit to using carbon dioxide because the gas has minimal physiological effect. There is also the benefit that the bubbles can be created as needed. There are several difficulties with this method, however. First, access has to be gained to the particular vessel to be imaged, because bubbles of carbon dioxide will not reliably travel through the lungs. Second, there is no way to measure or monitor the number or size distribution of the bubbles being created. Furthermore, as the patent concedes, a wide range of large bubbles is created. If these bubbles were created with any gas other than carbon dioxide, they would represent a significant hazard to the patient, as it would pose a risk of embolization or blockage of vessels and capillaries downstream. Lastly, if there is any failure, large bubbles of CO2 might be created in the blood vessel. Because carbon dioxide dissolves reasonably quickly, the bubbles are not likely to produce serious symptoms or tissue damage. They can, however, disturb the flow of blood and thus disrupt the imaging procedure. Thus, there are significant drawbacks and limitations to the apparatus and method disclosed by Daum et al.